Abstract Human caliciviruses are now the leading cause of viral gastroenteritis in children following introduction of rotavirus vaccines. While a great deal of data are emerging on the epidemiology and immunology of norovirus, a well-known calicivirus, similar data do not exist for sapovirus, a largely unknown and unstudied calicivirus. Importantly, sapovirus is gaining recognition as an important gastrointestinal pathogen in children. Data from recently published studies indicate sapovirus prevalence can range as high as 12 to 24% in children under five years of age with gastroenteritis. Furthermore, a recent re-analysis of the multi-site MAL-ED cohort samples found that sapovirus had the highest attributable fraction for diarrhea among all enteropathogens in infants. Given the importance of sapovirus among children with gastroenteritis, data are urgently needed to guide control and prevention strategies. For this proposal, we will investigate the natural history, development of immunity, and transmission dynamics of sapovirus in a cohort of 400 Nicaraguan children followed from birth until three years of age. Extensive questionnaire data, biological specimens (i.e., stool, serum, saliva, and breast milk), geographic coordinates, and environmental samples will be collected at baseline and regularly (weekly or monthly) during 36 months of follow-up. Because human sapovirus strains are unculturable, our team will also develop new virus-like particles (VLPs) for common sapovirus genotypes in order to measure anti-sapovirus IgA and IgG antibody concentrations in collected samples. In addition, cutting-edge laboratory techniques will be used in combination with epidemiologic data to investigate the course of sapovirus infections among children in the cohort, their households, and their communities. Nicaragua provides an ideal site to execute this study of the natural history, immunology, and transmission dynamics of sapovirus, because of the high incidence of sapovirus gastroenteritis in children under 5 years, the robust research infrastructure at the proposed site, and a long- standing collaboration between the University of North Carolina (UNC) and the University of Nicaragua (UNAN). In addition to leveraging this pre-existing collaboration, we have joined with calicivirus expert, Dr. Jan Vinj, who will provide content expertise for the study and will carry out some of the laboratory analyses in his lab at the Centers for Disease Control and Prevention. We are also forming a new collaboration with NIH-funded investigators who are conducting a parallel research study of childhood viral gastroenteritis in Peru, where the incidence of norovirus, but not sapovirus, is high. Together, this unique collaboration affords us the ability to exchange research and analytic tools to better understand the epidemiology and immunology of viral gastroenteric pathogens in young children. Specifically, this new research proposal will generate novel data that are fundamental for the advancement of control and prevention interventions, including future sapovirus vaccine development.